Novel 99mTc(III) Complexes as SPECT Radiotracers for MPI

描述（由申请人提供）：在本项目中，我们将评估8种新型99mTc（III）配合物[99mTc(S-R)(CDO)(CDOH)2B-Me] （R = P1 - P24）作为SPECT放射性示踪剂心肌灌注成像。采用SD大鼠评价其心脏摄取和生物分布。这些研究旨在回答以下三个基本问题：(1)它们是否能够在心脏中定位和保留（高心脏摄取和长心肌保留）？(2) PEG组对99mTc放射性示踪剂的心脏摄取和肝脏清除率有何影响？(3)哪种示踪剂对心脏摄取、心肌保留和心脏/肝脏比值最好？该项目的主要目的是增加心肌潴留，减少新型99mTc（III）放射性示踪剂的肝脏摄取，同时保持其高心脏摄取。假设和策略：我们假设硫代酸盐能够通过阻止其体内水解来增加其99mTc（III）复合物[99mTc(S-R)(CDO)(CDOH)2BMe] （R = P1 - P24）的心肌保留，因为硫代酸盐- s与Tc（III）形成比Cl更强的键。我们还假设聚醚组会增加99mTc（III）复合物的心肌保留和肝脏清除，因为PEG组可以增加治疗药物的血液保留时间，我们的研究清楚地表明聚醚组能够提高阳离子99mTc放射性示踪剂的肝脏清除。为了验证这些假设，我们制定了一个两步走的策略。第一步制备配合物[99mTc(S-R)(CDO)(CDOH)2B-Me] （R = P1 - P24）。使用不同的R基团来平衡它们的亲脂性，以便它们的心脏摄取和T/B比率可以系统地优化。第二步，我们将评估它们在SD大鼠中的心脏摄取和生物分布。99mt -替博肟将始终用作对照以进行比较。这些研究的结果将使我们能够选择一个最佳的候选人在未来进一步的评估。临床意义。目前有超过7000万美国人患有心血管疾病，每年有901万人死于心血管疾病。快速和准确的诊断对冠心病患者是非常可取的，这样可以给予适当的治疗方案。该项目的资金和成功完成可能会导致新的99mTc放射性示踪剂，具有非常高的第一次提取分数，心脏/肝脏比率远远优于99mTc- teboroxme。高心脏摄取和更好的心脏/肝脏比率将允许早期获取图像，并通过减少肝脏放射性散射提高图像质量。高首过率提取和血流速率与放射性示踪剂心肌摄取之间的线性关系将允许更好地检测冠状动脉疾病的存在和程度，并更精确地描述心肌灌注缺陷，这对已知或疑似CAD患者的管理和评估未来心脏事件的风险，特别是心肌梗死和死亡具有相当大的益处。

DESCRIPTION (provided by applicant): In this project, we will evaluate 8 novel 99mTc(III) complexes [99mTc(S-R)(CDO)(CDOH)2B-Me] (R = P1 - P24) as SPECT radiotracers myocardial perfusion imaging. Sprague-Dawley (SD) rats will be used to evaluate their heart uptake and biodistribution. These studies are designed to answer the following three fundamental questions: (1) Are they able to localize and retain in heart (high heart uptake and long myocardial retention)? (2) What is the impact of PEG groups on heart uptake and liver clearance of 99mTc radiotracers? (3) Which is the best radiotracer with respect to the heart uptake, myocardial retention and heart/liver ratios? The main objective of this project is to increase the myocardial retention and minimize liver uptake of novel 99mTc(III) radiotracers while maintaining their high heart uptake. Hypothesis and Strategy: We hypothesize that thiolates are able to increase the myocardial retention of their 99mTc(III) complexes [99mTc(S-R)(CDO)(CDOH)2BMe] (R = P1 - P24) by preventing their hydrolysis in vivo because thiolate-S forms a stronger bond with Tc(III) than Cl. We also hypothesize that polyether groups will increase the myocardial retention and liver clearance of 99mTc(III) complexes since it has been well-established that PEG groups can increase the blood retention times of therapeutics, and our studies clearly showed that polyether groups are able to improve liver clearance of cationic 99mTc radiotracers. To test these hypotheses, we developed a two-step strategy. In first step, we will prepare complexes [99mTc(S-R)(CDO)(CDOH)2B-Me] (R = P1 - P24). Different R groups are used to balance their lipophilicity so that their heart uptake and T/B ratios can be optimized in a systematic fashion. In the second step, we will evaluate their heart uptake and biodistribution in SD rats. 99mTc-Teboroxime will be always used as the control for comparison purposes. The results from these studies will allow us to select an optimal candidate for further evaluations in the future. Clinical Significance. More than 70 million Americans currently live with cardiovascular diseases, which lead to >910,000 deaths each year. Rapid and accurate diagnosis in CAD patients is highly desirable so that appropriate therapeutic regimens can be given. Funding and successful completion of this project may lead to new 99mTc radiotracers that have very high first-pass extraction fraction with the heart/liver ratios much better than tha of 99mTc-Teboroxime. High heart uptake with better heart/liver ratios will allow for early acquisition of images, and improve the image quality by reducing scatter from liver radioactivity. High first-pass extraction and linear relationship between the blood flow rate and the radiotracer myocardial uptake will permit better detection of the presence and extent of coronary disease, and more precise delineation of myocardial perfusion defects, which is of considerable benefit in management of patients with known or suspected CAD and assessing risk of future cardiac events, particularly myocardial infarction and death.